In this revised re-submission of our study of children at familial risk for depression (and controls), we have responded to the concerns of the IRG and revised our protocol accordingly. As we explicate, cognitive flexibility has been regarded as one component of executive function, which can be indexed as the ability to re- focus/shift attention and rapidly change cognitive sets in response to environmental demands. We now link our index of cognitive (in)flexibility to traditional cognitive risk factors for depression, and also incorporate an index of physiological flexibility, namely cardiac vagal control (CVC). Parental depression is a significant risk factor for major depressive disorder (MDD) in juveniles and also increases the odds of comorbid non-affective disorders. In the tradition of psychiatric high-risk family studies, we propose to examine combinations of selected personal characteristics as predictors of MDD and conduct and/or substance use-related disorders in juveniles at familial risk for depression. The personal characteristics include parental clinical (e.g., severity of mood disorder history) and child neurocognitive attributes (impaired cognitive flexibility). Cognitive flexibility as an executive function will be assessed both by traditional neuropsychological tests and their novel modifications which incorporate emotionally distracting features. As our Primary Aims, we will test hypotheses about the how the confluence of child and parent factors affect risk of MDD and non-affective disorders in offspring. Our sample will consist of n= 250 youths, including offspring of proband parents (who themselves had childhood-onset mood disorder) and offspring of control parents with no history of major psychiatric disorders. As our Secondary Aims, we will explore the relations of 2 traditional cognitive risk factors (ruminative response style and negative attributional style) to cognitive inflexibility, and the extent to which physiologic inflexibility (reflected in dysfunctional CVC) adds incremental information to our predictive model involving neurocognitive-clinical variables. Offspring will be 8-to-16-years old at initial assessment and 10-to- 18-years old at follow-up; this age range covers the transition into and across adolescence, which is the high risk period for MDD incident (new onset) cases and conduct/substance use related disorders. The feasibility of this study is underscored by the fact that we have access to a unique and well-maintained sample of families that had been ascertained as part of a prior Program Project on depression. Our study: a) is innovative because it integrates developmental and neurocognitive perspectives in the context of a high-risk family design and targets a cognitive process that may underlie a range of information processing biases in depression, b) has great public health significance because depression is both a personally devastating condition and a leading cause of disability worldwide, which may possibly be prevented or forestalled based on a better understanding of person-specific risk factors/mechanisms, and c) is timely because it reflects several components of NIMH's Strategic Objectives for research on mental disorders. PUBLIC HEALTH RELEVANCE: Although parental depression increases the odds of depression and other (non-mood) psychiatric disorders in young offspring, not all children who are at such familial risk become affected. We will therefore investigate whether certain parental clinical characteristics and child neuropsychological characteristics (impaired cognitive flexibility) predict major depressive disorder (MDD) and conduct/substance use-related disorders in 10-18 year-old offspring at familial risk for depression. In this study, cognitive flexibility refers to the ability to re-focus/switch attention and to rapidly change cognitive sets in response to environmental demands; it will be assessed both by traditional neuropsychological tests and novel modifications of such tests which incorporate emotionally distracting features. We also will examine how cognitive (in)flexibility relates to more traditional cognitive risk factors for depression and whether including an index of physiologic (in)flexibility will improve our predictive models. Our study: a) is innovative because it integrates developmental psychopathology and neurocognitive perspectives in the context of a high-risk family design and targets a cognitive process that may underlie information processing biases in depression, b) has considerable public health significance because a better understanding of person-specific risk factors/mechanisms may pave the way for targeted prevention of depression, which is both personally devastating and a leading cause of disability worldwide, and c) is timely because it reflects NIMH's Strategic Objectives for research on mental disorders.